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P60, a Foxp3 inhibitory peptide, can hinder the regulatory T cell (Treg) activity and impair tumor proliferation. However, low systemic stability and poor specificity have led to daily dosing to achieve therapeutic effect. Therefore, this study aims to improve P60 stability and specific delivery through its encapsulation in liposomes targeting CD25, constitutively expressed in Tregs. P60 liposomes formulated with DSPE-PEG750 or DSPE-PEG2000 were incubated with DSPE-PEG2000-Maleimide micelles conjugated to Fab' fragments of anti-CD25 to develop two targeted formulations or immunoliposomes (IL): IL-P602000 (DSPE-PEG2000 only) and IL-P60750 (combining DSPE-PEG750 and DSPE-PEG2000). P60 encapsulation efficiency was 50%-60% irrespective of PEG chain length. Treg uptake was 2.5 and 14 times higher for IL-PEG750 compared with IL-PEG2000 and non-targeted liposomes, respectively, in in-vitro assays. In fact, IL-P60750 allowed CD8+ T cells ex-vivo proliferation in presence of Treg at doses 10-20 times lower than for free P60. Antitumor response of P60 and IL-P60750 in monotherapy and combined with anti-PD-1 was evaluated in MC38 and LLCOVA tumor bearing mice. In MC38 model, IL-P60750 monotherapy induced total tumor regression in 40% of mice reaching 100% for anti-PD-1 combination. This effect was associated with a significant increase in activated CD8+ T cells in tumors. Notably, IL-P60750 also inhibited human Treg in ex-vivo assay, showing the translational capability of this formulation. In conclusion, IL-P60750 formulated with different PEG chain lengths, has demonstrated antitumor efficacy by selective inhibition of Treg activity and enhances the effect of anti-PD1. Altogether, this novel IL represents a promising nanoplatform for cancer immunotherapies.
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BACKGROUND: Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment. METHODS: In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry. RESULTS: The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8+ T lymphocytes at day 8. Depletion of either myeloid cells or CD8+ T lymphocytes diminished the anti-tumour efficacy of the combination. CONCLUSIONS: The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
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Anticuerpos Monoclonales/farmacología , Células Mieloides/inmunología , Neoplasias/inmunología , Fragmentos de Péptidos/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor Toll-Like 3/metabolismo , Animales , Proliferación Celular , Combinación de Medicamentos , Femenino , Humanos , Ligandos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Células Mieloides/patología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab') of α-PD-L1. RESULTS: Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1+ cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site. CONCLUSION: PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.
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Antineoplásicos/farmacología , Antígeno B7-H1/metabolismo , Doxorrubicina/farmacología , Inmunidad/efectos de los fármacos , Liposomas/inmunología , Melanoma/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Liberación de Fármacos , Quimioterapia , Femenino , Inmunoterapia/métodos , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BLRESUMEN
Immunoliposomes (ILs), obtained with monoclonal antibodies (mAbs) decorating the liposome surface, are used for cancer treatment. These mAbs provide the recognition of molecules upregulated in cancer cells, like Programmed Death-Ligand 1 (PD-L1), an immune-checkpoint involved in tumor resistance, forming a complex that blocks this molecule and thereby, induces antitumor immune response. This mechanism introduces a new concept for ILs. ILs coupled to anti-PD-L1 or its Fab' fragment have been developed and in vitro/in vivo characterized. Factors such as coupling methods, PEG density and ligand size were optimized. In vitro data showed that Fab'-ILs displayed the highest PD-L1 cell interaction, correlating with a higher in vivo tumor accumulation and an increase of effector cytotoxic CD8+ T cells, providing tumor shrinkage and total regression in 20% of mice. Therefore, a novel immune-nanoplatform able to modulate the immune system has been developed, allowing the encapsulation of several agents for combinatorial therapies.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Femenino , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunoterapia , Liposomas , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunologíaRESUMEN
The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.
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Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Ciclo Celular , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/patología , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Camptotecina/farmacología , Proliferación Celular , Ensayos Clínicos Fase I como Asunto , Esquema de Medicación , Humanos , Neoplasias/patología , Neutropenia/sangre , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Células Madre/efectos de los fármacos , Células Madre/patologíaRESUMEN
Monoclonal antibodies (mAbs) represent a therapeutic strategy that has been increasingly used in different diseases. mAbs are highly specific for their targets leading to induce specific effector functions. Despite their therapeutic benefits, the presence of immunogenic reactions is of growing concern. The immunogenicity identified as anti-drug antibodies (ADA) production due to the continuous administration of mAbs may affect the pharmacokinetics (PK) and/or the pharmacodynamics (PD) of mAbs administered to patients. Therefore, the immunogenicity and its clinical impact have been studied by several authors using PK modeling approaches. In this review, the authors try to present all those models under a unique theoretical mechanism-based framework incorporating the main considerations related to ADA formation, and how ADA may affect the efficacy or toxicity profile of some therapeutic biomolecules.
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Anticuerpos Antiidiotipos/análisis , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Modelos Inmunológicos , Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales/efectos adversos , HumanosRESUMEN
Immunotherapy has become an important part of the oncotherapy arsenal. Its applicability in various cancer types is impressive, as well as its use of endogenous mechanisms to achieve desired ends. However, off-target or on-target-off-tumor toxicity, limited activity, lack of control in combination treatments and, especially for solid tumors, low local accumulation, have collectively limited clinical use thereof. These limitations are partially alleviated by delivery systems. Lipid-based nanoparticles (NPs) have emerged as revolutionary carriers due to favorable physicochemical characteristics, with specific applications and strengths particularly useful in immunotherapeutic agent delivery. The aim of this review is to highlight the challenges faced by immunotherapy and how lipid-based NPs have been, and may be further utilized to address such challenges. We discuss recent fundamental and clinical applications of NPs in a range of areas and provide a detailed discussion of the main obstacles in immune checkpoint inhibition therapies, adoptive cellular therapies, and cytokine therapies. We highlight how lipid-based nanosystems could address these through either delivery, direct modulation of the immune system, or targeting of the immunosuppressive tumor microenvironment. We explore advanced and emerging liposomal and lipid nanoparticle (LNP) systems for nucleic acid delivery, intrinsic and extrinsic stimulus-responsive formulations, and biomimetic lipid-based nanosystems in immunotherapy. Finally, we discuss the key challenges relating to the clinical use of lipid-based NP immunotherapies, suggesting future research directions for the near term to realize the potential of these innovative lipid-based nanosystems, as they become the crucial steppingstone towards the necessary enhancement of the efficacy of immunotherapy.
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Inmunoterapia , Lípidos , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Nanopartículas/uso terapéutico , Nanopartículas/química , Lípidos/química , Animales , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Liposomas/químicaRESUMEN
Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically-based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.
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Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Virus Oncolíticos/genética , Distribución Tisular , Neoplasias/terapia , InmunidadRESUMEN
Nanoparticles (Nps) have revolutionized the landscape of many treatments, by modifying not only pharmacokinetic properties of the encapsulated agent, but also providing a significant protection of the drug from non-desired interactions, and reducing side-effects of the enclosed therapeutic, enabling co-encapsulation of possibly synergistic compounds or activities, allowing a controlled release of content and improving the therapeutic effect. Nevertheless, in systemic circulation, Nps suffer a rapid removal by opsonisation and the action of Mononuclear phagocyte system (MPS). To overcome this problem, different polymers, in particular Polyethyleneglycol (PEG), have been used to cover the surface of these nanocarriers forming a hydrophilic layer that allows the delay of the removal. These advantages contrast with some drawbacks such as the difficulty to interact with cell membranes and the development of immunological reactions, conforming the known, "PEG dilemma". To address and minimize this phenomenon, different strategies have been applied. Therefore, this review aims to summarize the state of the art of Pegylation strategies, comment in depth on the principal characteristics of PEG and describe the main alternatives, which are the use of cleavable PEG, addition of different polymers or even use other derivatives of cell membranes to camouflage Nps.
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Nanopartículas , Polietilenglicoles , Polímeros , Portadores de FármacosRESUMEN
Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
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Hidroximetilbilano Sintasa , Porfiria Intermitente Aguda , Animales , Modelos Animales de Enfermedad , Terapia Genética/métodos , Hidroximetilbilano Sintasa/metabolismo , Hidroximetilbilano Sintasa/uso terapéutico , Ratones , Porfiria Intermitente Aguda/tratamiento farmacológico , Porfiria Intermitente Aguda/metabolismoRESUMEN
Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-based strategies targeting cancer immune evasion and modulating the immunosuppressive tumor microenvironment, including the inhibition of immunosuppressive cells in the tumor area, the activation of dendritic cells and the stimulation of the specific antitumor T-cell response.
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V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t1/2 = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.
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Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
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PURPOSE: To develop a semi-physiological-based model describing simultaneously the time course of immature and mature B-lymphocytes after topotecan (TPT) administration to tumor-bearing rats. METHODS: Twenty-four tumor-bearing BDIX male rats received a single 6 mg/kg intra-peritoneal dose of TPT or saline. Mature and immature B-cell levels were measured every two days during three weeks and showed a very different temporal pattern. Both B-cell populations declined rapidly, reaching the nadir at 3-4 days after TPT administration; however, mature cells returned to baseline at day 8, while immature B-cells stayed at nadir until day 9 instead. Data were modeled using the population approach with NONMEM VI. RESULTS: The model developed maintains the proliferation, maturation and degradation elements of previous published models for myelosuppresion. In order to describe the rapid recovery of mature cells, it includes a peripheral compartment providing a constant supply of mature cells to the bloodstream. CONCLUSIONS: The major contribution of the model is its new structure and the dynamical consequences, demonstrating an independent behavior between mature and immature B-cells during recovery. The final model could represent a good basis for the optimization of cytotoxic drugs oriented to attain a maximum antitumor efficacy while minimizing hematological toxicity.
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Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Linfocitos B/efectos de los fármacos , Topotecan/farmacología , Topotecan/farmacocinética , Animales , Linfocitos B/citología , Masculino , Modelos Biológicos , RatasRESUMEN
BACKGROUND AND OBJECTIVE: Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustained-release formulation lanreotide Autogel after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. SUBJECTS AND METHODS: This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 microg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel at a dose of 60, 90 or 120 mg. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM((R)) version VI software. The model was validated externally using data from patients with acromegaly. RESULTS: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel was 63%. The rate of absorption and bioavailability of lanreotide Autogel were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05). CONCLUSIONS: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 microg/kg) and the pharmacokinetics of lanreotide Autogel after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel was independent of the dose and was not affected by sex.
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Péptidos Cíclicos/farmacocinética , Somatostatina/análogos & derivados , Adolescente , Adulto , Femenino , Geles , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Modelos Biológicos , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/efectos adversos , Somatostatina/administración & dosificación , Somatostatina/efectos adversos , Somatostatina/farmacocinéticaRESUMEN
OBJECTIVES: To explore the performance of the National Comprehensive Cancer Network Distress Thermometer (DT) as a distress screening tool in cancer survivors. SAMPLE & SETTING: 236 Spanish adult-onset cancer survivors who visited the Fundación Instituto Valenciano de Oncología in Valencia, Spain, for follow-up appointments. METHODS & VARIABLES: Survivors completed the DT and the Brief Symptom Inventory 18 (BSI-18), which has established a cutoff score for identifying clinically significant distress. RESULTS: Receiver operating characteristic curve analysis of the DT scores relative to the BSI-18 cutoff score showed good overall accuracy. For a score of 5 or greater, sensitivity, specificity, positive predictive value, negative predictive value, and clinical utility indexes indicated that the DT appeared to be satisfactory for screening but had restricted use for case finding. IMPLICATIONS FOR NURSING: Screening for and responding to distress is considered an important part of nursing practice. The DT is suitable for use as a first-stage, quick-detection instrument in a two-step screening process to rule out noncases among Spanish post-treatment cancer survivors.
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Supervivientes de Cáncer/psicología , Psicometría/normas , Estrés Psicológico/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , España , TraduccionesRESUMEN
The present study evaluates the potential of encapsulated doxorubicin to reduce both the viability of melanoma cells and the tumor growth in a mouse melanoma model. The prepared doxorubicin loaded chitosan/alginate nanoparticles possessed mean diameter around 300â¯nm and negative zeta-potential. Classical molecular dynamic simulations revealed that the high encapsulation efficiency (above 90%) was mainly due to electrostatic interaction between doxorubicin and sodium alginate, although dipole-dipole and hydrophobic interactions might also contribute. The in vitro dissolution tests showed slower doxorubicin release in slightly alkaline medium (pHâ¯=â¯7.4) and faster release in acid one (pHâ¯=â¯5.5), indicating that higher concentration of doxorubicin might reach the acidic tumor tissue. The free and the encapsulated doxorubicin decreased the viability of melanoma cell lines (B16-F10 and B16-OVA) in a similar degree. However, the cytotoxic effect of the encapsulated doxorubicin still occurred in the more resistant B16-F10 cells even after removing the extracellular drug. The experiments on a syngeneic melanoma mouse model revealed that free and encapsulated doxorubicin elicited the control of the tumor growth (dose of 3â¯mg/kg). Thus, the encapsulation of doxorubicin into chitosan/alginate nanoparticles could be considered advantageous because of the better intracellular accumulation and longer cytotoxic effect on the investigated melanoma cells.
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Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Melanoma Experimental/tratamiento farmacológico , Nanopartículas , Alginatos/química , Animales , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica/métodos , Quitosano/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Femenino , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Tamaño de la PartículaRESUMEN
Biodegradable lactic acid-glycolic acid copolymer (PLGA) formulations incorporating cisplatin have been developed to evaluate the cytotoxicity of this agent in cultured cells. Two different W/O/W protocols were used to formulate micro- (MP) and nanoparticles (NP) under the solvent evaporation method. Although the amount of cisplatin encapsulated was higher in the MP, the efficiency of encapsulation was similar: 10.33% vs. 11.23%, for both MP and NP, respectively. The "in-vitro" release profiles displayed a significant difference in the initial burst effect, which had a significant impact in the antiproliferative effect of cisplatin. In addition, a duality in the cell cycle distribution was found for both formulations and low doses of free cisplatin (2.5, 10 microM) in comparison with the high doses of free cisplatin. The 50 microM caused a rapid inhibition of cells growth followed by a significant loss of cells in phases G0/G1 and G2/M which correlated with an increase in the number of cells in sub-G1. However, cisplatin released from controlled formulations induced an accumulation of cells in the phase G2/M. These results led to enhance the caspase-3 activity for MP and NP. These findings indicate that controlled release formulations of cisplatin are able to induce a more effective apoptosis than free cisplatin.
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Cisplatino/administración & dosificación , Cisplatino/farmacología , Ácido Láctico/administración & dosificación , Ácido Poliglicólico/administración & dosificación , Animales , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Preparaciones de Acción Retardada , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , RatasRESUMEN
The aim of the present work was to describe the antiproliferative effect of camptothecin (CPT), topotecan (TPT) and cisplatin (CIS) in cultured cells using a semi-mechanistic pharmacodynamic approach. This effect on the growth of DHD-K12PROb cells was modelled as a function of drug concentration and time of exposure using the Gompertz framework. Models reflected two major processes: cell proliferation and cell death/degradation. Antiproliferative effect of CPT and TPT was described as inhibition of cell proliferation, while the effect of CIS was described as stimulation of cell death, including a signal transduction process, reflected as a delay in the onset of drug action. The half-life associated with such a transduction process was estimated to be approximately 27 h. Interestingly, the time profiles of the model predicted a signal transduction process that closely resembled the observed profiles of caspase-3, a protein implicated in CIS-mediated apoptosis. Therefore, the combination of a simple and sensitive design, together with an appropriated modelling strategy, allowed us to explore different mechanisms of action for antitumour agents in cultured cells and to obtain information about the dynamics of signal transduction and the potential use of biomarkers.
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Algoritmos , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Animales , Camptotecina/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Ratas , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Topotecan/farmacologíaRESUMEN
Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab', to the polymers covering the surface of liposomes. The combination of this targeting strategy together with drug encapsulation in a single formulation may contribute to enhance the efficacy of these associated agents, reducing their toxicities. In this paper we will consider how factors such as particle size, lipid composition and charge, lipid-polymer conjugation, method of production and type of ligand for liposome coupling influence the efficacy of these formulations. Furthermore, the high inter-individual variability in the tumor microenvironment, as well as the poor experimental designs for the PK characterization of liposomes, make the establishment of the relationship between plasma or tumor concentrations and efficacy difficult. Thus, adequate dosing regimens and patient stratification regarding the target expression may contribute to enhance the possibility of incorporating these immunoliposomes into the therapeutic arsenal for cancer treatments. All these issues will be briefly dealt with here, together with a section showing the state of the art of those targeted liposomes that are coming up for testing in clinical trials. Finally, some insights into future developments such as the combination of specificity and controlled release, based on the application of different stimuli, for the manipulation of stability and cargo release, will be offered. This has been included in order to highlight the new opportunities for targeted liposomes, including immunoliposomes.